MX2007015895A - Stable buffered, pharmaceutical compositions including motilin-like peptides. - Google Patents

Abstract

Stable, pharmaceutical compositions including a synthetic motilin-like peptide in a buffered solution are disclosed. The composition provides for a peptide that remains stable and substantially retains its initial potency during extended storage and after steam sterilization.

Description

PHARMACEUTICAL COMPOSITIONS. AMQRTDGUAi STABILITY THAT INCLUDES PEPTBDOS TAPO MOTIL! Cross Reference with Related Requests This application claims the benefit of the Request Provisional North American Number 60 / 691,555, filed June 17, 2005, the contents of which are incorporated herein by reference. Field of the Invention) The present invention relates to pharmaceutical compositions that include a motilin-like peptide. More particularly, the present invention relates to pharmaceutical compositions that include a motilin-like peptide that remains stable and retains its potency and binding affinity after prolonged storage periods. BACKGROUND OF THE INVENTION Motilin peptide is a linear gastrointestinal polypeptide hormone, which stimulates gastrointestinal motor activity in mammals. Motilin plays an important role in the increase of gastric motility, regulating the interdigestive myoelectric complex. The administration of motilin to human subjects accelerates intestinal transit and increases gastric emptying [Christofides et al., Gastroenterology 76. 903-907 (1979)]. In vitro studies have showed that motilin stimulates the contractions of duodenal smooth muscle bands and gastrointestinal smooth muscle cells isolated from humans and mice. Motilin has been reported to stimulate the emptying of solids and liquids in patients with diabetic gastroparesis [Peeters et al., Gastroenteroloy 100, A480 (1991)], and has been used to treat patients with paralytic ileus originating from carcinoma of the gastrointestinal tract [Meyer et al. Associates, Med. Klin. 86, 515-517 (1991)]. One of the disadvantages of motilin is its relatively short half-life in vivo (Christofides, 1979, op.cit.), Which makes it necessary to administer the hormone by continuous infusion in order to induce a therapeutic effect. synthetic motilin peptides which mimic motilin activity while possessing improved metabolic stability These peptides are reported and described in U.S. Patent Number 5,422,341, which is incorporated herein by reference.The synthetic motilin-like peptides described in US Pat. The patent North American Number 5,422,341, have been shown to be effective in stimulating gastrointestinal activity, and demonstrate increased stability to biodegradation in tissue homogenates of relevant organs. However, as with motilin that occurs naturally, synthetic motilin compounds they are potentially subject to rapid degradation of the peptide due to hydrolysis, oxidation or other chemical processes before administration. Motilin and synthetic motilin compounds in solutions containing low concentrations can be unstable during storage, even when stored in sealed containers. It is known that certain peptides that are otherwise prone to degradation during storage can be stabilized, and therefore stored for prolonged periods without loss of biological activity, by preparing the peptide as an aqueous composition. For example, U.S. Patent No. 5,482,931, discloses an aqueous composition for administration of peptides such as oxytocin, vasopressin and analogs and derivatives thereof, which can maintain stability over time at room temperature. The solution contains a buffer, a preservative or quaternary amine disinfectant and an osmotic control agent. According to US Patent Number 5,482,931, the aqueous peptide composition retained useful shelf life after several weeks of storage at room temperature. Other examples of stable peptide aqueous formulations are described in U.S. Patent Nos. 5,916,582 and 6,068,850. These patents describe formulations High-concentration hormone release hormone (LHRH) hormone peptides are aqueous, which can be stored at elevated temperatures (eg, 37 ° C) for prolonged periods of time. An example of a "stable" motilin composition is described in EP 437,621 A1. Aqueous motilin solutions and freeze-dried compositions showed stability in a solution at a pH of 4.0-5.5. The motilins described in the present invention included canine motilin, pig motilin, human motilin and certain motilin derivatives (for example, pork motilin-13leucine). These motilins and motilin derivatives retained approximately 94% motilin content after 7 days of storage at a temperature of 60 ° C. Although the prior art recognizes that the stabilizing effect of certain solutions on selected peptides, and EP 437,621 A1 suggests that inactive motilin (total length) can be prepared in the form of stable freeze-dried or aqueous compositions, the results provided therein do not anticipate how other motilin derivatives or motilin-like peptides may behave in aqueous solutions or similar lyophilized compositions. This is because certain differences in the structure of peptides and the existence or absence of charged functional groups and acid / base of a given peptide can affect significantly the solubility, pH / solubility profile, isoelectric point and pKa values, thus making a peptide sufficiently different from other related peptides. Accordingly, it can not be accurately anticipated whether a stable aqueous or lyophilized formulation of a motilin derivative can be prepared. As described in U.S. Patent Number 5,422,341, motilin-like peptides are structurally distinct from active motilin. These structural differences, which are described in more detail below, make it difficult to determine whether the motilin-like peptide can retain its stability in an aqueous or lyophilized solution. Due to the advantages described above provided by the motilin-like peptides, it may be desirable to provide aqueous pharmaceutical compositions that include such motilin-like peptides. It may also be desirable to provide compositions that include motilin-like peptides that can be administered to a patient after long-term storage. In addition, it may be desirable to provide compositions that substantially prevent degradation of the motilin-like peptide, although maximum levels of potency of the compound are maintained during the storage period. It may be desirable to provide a composition of Ready-to-use aqueous peptide that remains stable (and maintains potency) after storage under ambient temperature conditions, as well as after exposure to elevated temperatures, such as, but not limited to, the temperature of steam sterilization. It may be desirable to provide such synthetic motilin-like peptides as aqueous compositions in various concentrations or in lyophilized form. Finally, it may be desirable to provide a composition that includes a synthetic motilin-like peptide that, if necessary, can be stored and remain stable for extended periods of time in any of the various different containers. Brief Description of the [Invention] In one aspect, the present invention is directed to pharmaceutical compositions comprising about 0.5 μg / ml to 100 mg / ml of a synthetic motilin-like peptide having no more than 16 amino acids and the structure described further ahead. Said compositions further include 5-250 mM of a buffer, and have a pH of between 3 and 9 and an osmolarity of about 10-500 mOsm / kg. In a further aspect, the present invention is directed to compositions that include the synthetic motilin-like peptide that can be sterilized by steam sterilization at a temperature of 120 ° C-128 ° C, wherein the peptide retains at least about 95% of its initial power.

In a further aspect, the present invention is directed to ready-to-use pharmaceutical compositions that include the synthetic motilin peptide, wherein the peptide can be stored for at least 18 months at a temperature of -37 ° C, and retains at least about 90% of its initial power. In a further aspect, the present invention is directed to compositions that include a motilin-like synthetic peptide having the structure described below that includes no more than 16 amino acids, wherein the composition is provided in a concentrated form that includes a selected amount. of peptide and buffer, whereby at the time of dilution the aqueous composition includes 0.5 μg / ml-100 μg / ml of the peptide, 10-100 mM of a buffer, which has a pH of between 3-9 and an osmolarity of approximately 10-500 mOsm / kg. In yet a further aspect, the present invention is directed to lyophilized compositions that include a motilin-like synthetic peptide having the structure described below and including no more than 16 amino acids, whereby at the time of reconstitution, the composition reconstituted includes 0.5 μg / ml-100 μg / ml of the peptide and has a pH between 3-9 and an osmolarity of about 10-500 mOsm / kg. Optionally, the composition may also include 10-200 mM of a shock absorber. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the stability of the peptide in a composition representing the present invention, in storage up to 24 months. Figure 2 is a graph showing the stability of the peptide in a composition representing the present invention after autoclaving. Figure 3 is a graph showing the stability profile of the motilin-like synthetic peptide at a concentration of 5 μg / ml in a composition representing the present invention when stored in a selected glass container. Figure 4 is a graph showing the stability profile of the motilin-like synthetic peptide at a concentration of 30 μg / ml in a composition representing the present invention when stored in a selected glass container. Figure 5 is a graph showing the stability of the peptide in a composition representing the present invention after storage, wherein the composition is lyophilized, stored in its lyophilized form and reconstituted in a subsequent manner. Detailed Description of the Bnvention The pharmaceutical compositions of the present invention they include a motilin-like synthetic peptide that may be effective in the treatment of gastrointestinal disorders, but is not limited to, post-operative ileus, diabetic gastroparesis and paralytic ileus. The pharmaceutical compositions of the present invention include a motilin-like synthetic peptide, or a pharmaceutically acceptable salt thereof, in a selected buffer at a selected concentration. The pharmaceutical compositions have a pH and osmolarity also selected to maintain the stability of the peptide over a prolonged period of time. The pharmaceutical compositions of the present invention remain stable during long-term storage, such as at least 12 months, and preferably at least 18 months, and up to 24 months at temperatures commonly encountered during storage, such as, but not limited to, between approximately 4 ° C and approximately 30 ° C. The pharmaceutical compositions of the present invention show minimal degradation and loss of peptide potency during said periods of time and at said temperatures. The motilin-like peptide of the pharmaceutical compositions of the present invention remains chemically stable and biologically potent even after exposure to elevated temperatures, such as, but not limited to, steam sterilization temperature (eg, 121 ° C). As used in the present invention, the references to stability refer to the degree of peptide degradation and residual potency of the peptide, as determined by biological assays. For example, a motilin-like peptide that is 95% non-degraded after storage, as determined by chemical purity analysis, retains 95% potency in biological assays. In the pharmaceutical compositions of the present invention, the motilin-like peptide is not substantially degraded and remains substantially potent and effective in the treatment of gastrointestinal disorders. The pharmaceutical compositions of the present invention include, in general, a selected amount of a motilin-type synthetic polypeptide. The synthetic peptide may be a motilin-like peptide that is effective in treating or stimulating gastrointestinal motor activity. Motilin-type peptides to stimulate gastrointestinal activity show a high affinity with the motilin receptor. Examples of such motilin polypeptides are described in U.S. Patent Number 5,422,341, previously incorporated by reference, which discloses motilin-like synthetic peptide amino acid sequences. In a preferred embodiment of the present invention, the motilin-like synthetic peptide contained in the compositions of the present invention is truncated. Preferably, the Motilin-type synthetic peptide will normally include no more than 16 amino acids, and more preferably 11 to 16 amino acids. In one embodiment, the motilin-like peptide has the following structure: R2 Ri N- * CHCO-A-B-D-E-Thr-F-G-H-Leu-I-J-NH- * CHR6 R3 CH2R4 CH2R5 wherein: A is L-stereoisomer of a lipophilic aliphatic amino acid; B is L-proline or L-alanine; D is the L-stereoisomer of a lipophilic aliphatic amino acid; E is the L-stereoisomer of an aromatic amino acid, lipophilic aliphatic, or alicyclic; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine; J is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-GIn-Glu, Z-Leu-GIn-Glu-Lys, wherein Z is selected from the group consisting of D- arginine, D- homoarginine, D-glutamine, D-asparagine and D-alanine; Ri is lower alkyl or allyl; R2 is selected from the group consisting of hydrogen, lower alkyl, propargyl and allyl; R3 is selected from the group consisting of hydrogen, lower alkyl and allyl; R 4 is cycloalkyl or aryl which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and lower alkoxy; R5 is selected from the group consisting of --CH2 CONH2, aminoalkyl groups containing from 1 to 3 carbon atoms; and guanidinoalkyl groups containing from 2 to 3 carbon atoms; R6 is --COOH or --CONH2; and the symbol * represents an asymmetric carbon atom which may be in the D or L configuration, and wherein each lower alkyl group contains from 1 to 4 carbon atoms, provided that: (i) R5 is --CH2 CONH2 , only when J is Z-Leu; In a preferred embodiment, the peptide contained in a pharmaceutical composition of the present invention can additionally include D-Arginine at position 12. The peptide of the present invention can also include an N-term alkylated, and preferably, trialkylated (by example, methylated). In addition, the motilin-like synthetic peptide may include an amide group (-CONH2) in the acid functionality C-terminal carboxylic chain of the polypeptide chain, which changes the pKa profile and charge of the motilin-like peptide (as compared to native motilin) and is also considered to affect solubility. A particularly preferred embodiment of the present invention includes the motilin-type synthetic peptide receptor agonist, which includes SEQ ID NO: 1 and which is represented by the following formula: (Me3N) + Phe-Val-Pro-lle-Phe- Thr-Tyr-Gly-Glu-Leu-Gln-D-Arg-Leu-Lys-NH2, wherein the following abbreviations represent the amino acids: Phe-L-Phenylalanine Tyr-L-Tyrosine Leu-L-Leucine Val-L- Valine Pro - L - Proline Me - L - lucoseucine Thr - L - Threonine Gly - Glycine Glu - L - Glutamic Acid Gln - L - Glutamine D - Arg - D - Arginine Lys - L - Lysine. Motilin type peptides, which include SEQ ID NO: 1, are particularly effective and show improved stability, Prolonged potency and are suitable for autoclaving (described below) when said peptides are included in the compositions of the present invention. Also included within the scope of the present invention are all pharmaceutically acceptable salts of the peptide identified above. Other peptides, including those described in U.S. Patent Number 5,422,341, which are substantially similar to the peptide including SEQ ID NO: 1 described in the present invention, may also show improved stability in the compositions of the present invention. This may include, for example, other motilin-like synthetic peptides described in the referenced patents which have substantial homology (ie greater than 50% and preferably at least 60 to 70%) with the N-terminal sequence of the motilin peptide. human. The motilin-type peptide contained in the compositions of the present invention is provided in an amount of about 0.5 μg / ml to 100 mg / ml. More preferably, when the composition is "ready to be used" (ie, it does not require further dilution or reconstitution) the amount of motilin-like peptide can be between about 1 μg / ml and 1 mg / ml, even more preferably 1 μg / ml. ml-50 μg / ml and normally within the range of 1 μg / ml-30 μg / ml. Due to the potency of the peptides, the compositions of low concentration may be convenient in the controlled administration of the desired amount of the peptides. Of course, a more concentrated composition of the peptide, which represents a present invention, can be diluted to produce a solution for convenient administration. In one embodiment, when the composition is provided in a "ready-to-use" form, the motilin-type peptide is dissolved in a buffer solution to provide an aqueous composition. The buffer is selected to maintain the pH of the pharmaceutical composition between about 3 and 9, wherein the pH of the peptide shows substantially improved stability and retention of potency. More preferably, the pH of the pharmaceutical compositions is between about 4 and 6, more preferably 4.5 and 5.5 and most preferably between 4.8-5.2. At these pH levels, the SEQ. ID. 1, a preferred example of motilin-like peptide, shows only minimal degradation during storage. (The preferred pH of the composition can also be determined, in part, based on whether the composition is prepared as an aqueous composition or a lyophilized formulation, which is described below). Buffer solutions suitable for use with the pharmaceutical compositions of the present invention include buffers such as sodium acetate / acetic acid, sodium hydrogen phosphate buffers and sodium citrate / citric acid buffers. Other buffer systems known to those skilled in the art, such as, but not limited to, tartrate, succinate, TRIS, histidine and glycine can also provide adequate cushioning of the compositions within the pH range identified above. As indicated above, in one embodiment, the sodium acetate / acetic acid buffer is combined with the motilin-type peptide to provide an aqueous composition. When provided as a ready-to-use solution, the concentration of the buffer in the pharmaceutical composition can be between 5 and 250 mM, and more preferably between 5 and 50 mM, with a concentration of about 5-25 mM being most preferred for many of the modalities, to achieve and maintain the preferred pH. When the composition is provided as a concentrated solution requiring dilution, the concentration of buffer may be significantly higher, such as, but not limited to, up to 10 times more or up to 2-3 M. (In such concentrated solutions, the concentration of peptide will also be correspondingly higher). The subsequently concentrated compositions are diluted with a diluent to reach the concentration and amounts of preferred buffer (for example 5-250 mM) and peptides (for example 1 μg / ml-100 μg / ml) with a tonicity suitable for administration. Suitable, pharmaceutically acceptable diluents include, but are not limited to, sterile water, sterile sodium chloride solution, sterile dextrose solutions (eg, 5%) and other sugars, and the like. The aqueous pharmaceutical compositions of the present invention can be either hypotonic, substantially isotonic or hypertonic, having an osmolarity of between 10-500 mOsm. However, more preferably the composition is isotonic, or slightly hypotonic or slightly hypertonic, although hypotonic compositions with an osmolarity between 100 mOsm and even below 50 Osm, may also be effective. Normally, however, the tonicity of the pharmaceutical composition can be between 270-320 mOsm. The tonicity of the pharmaceutical composition can be adjusted using sodium chloride (NaCl) or other tonicity adjusting additives, such as glycerin, mannitol, sucrose and other reduced sugars, or other agents known to those skilled in the art, as necessary . Table 1, which follows, summarizes the preferred constituents and conditions of the pharmaceutical compositions of the present invention, both ready-to-use and concentrated forms.

In a preferred embodiment ready for use, the aqueous pharmaceutical compositions of the present invention include 1 μg / ml-100 μg / ml of the motilin-type synthetic peptide of SEQ. ID. No. 1 in about 10 mM sodium acetate / acetic acid buffer at a pH of about 4.8-5.2 and an osmolarity of about 300 ± 20 mOsm. In addition to aqueous compositions, ready-to-use or concentrated compositions requiring dilution, the composition of the present invention may also be stored in a lyophilized form (freeze-dried). The composition, in its lyophilized form, may include the relative amounts of the peptide and buffer set forth in Table 1 above (as well as other agents). It will be appreciated that when the composition has been stored in a lyophilized form, administration of the composition can occur immediately upon reconstitution, making the long-term storage stability of the reconstituted composition less critical, and therefore, optional the presence of a shock absorber. In any case, in one embodiment of the formulation used, the optional shock absorber it may be citrate / citric acid at a preferred pH of about 4.7 and more preferably 6.0. In addition, the formulation used may further include one or more bulking agents such as, but not limited to, sucrose, mannitol and glycine and / or combinations thereof. The volume generation agents can be included in a concentration of 0.5-15% w / v. The aqueous pharmaceutical compositions of the present invention provide the previously known benefits. The motilin-like peptide of the pharmaceutical compositions of the present invention remains stable when stored over a wide temperature range for extended periods of time. For example, when stored at room temperature or its preferred lower storage temperature of 4 ° C-5 ° C, substantial stability is maintained for significant periods of time. For example, at a storage temperature of about 25 ° C, the peptide contained in the composition of the present invention remains stable for at least 12 months, and more preferably at least about 18 months, and even more preferably, up to and including beyond about 24 months, retaining a power of 90% or more as shown, for example, in Figure 1. At a storage temperature of 5 ° C, storage is normally observed only with degradation marginal (and a power of at least 90-95%) for up to at least 18 months. A further advantage of the pharmaceutical composition of the present invention is its peptide stability when the composition is subjected to elevated temperatures such as the sterilization temperature. Many peptides are inherently unstable, and when subjected to heat, it is known to degrade very rapidly, usually in a few minutes or less. In contrast, in compositions of the present invention, the peptide substantially retains its stability (ie, remains substantially non-degradable and retains its substantial percentage of initial potency), even after the composition is (1) subjected to sterilization, (during at least 10 minutes and up to 60 minutes) at temperatures of about 100 ° C-128 ° C and usually 121 ° C), and (2) subsequently stored in a suitable container (described below) at lower temperatures usually found in a composition pharmaceutical, such as about 4 ° C-5 ° C to about 25 ° C. As shown in Figure 2, and described in Example 1 below, in samples of a pharmaceutical composition of the present invention that were subjected to steam sterilization in a Type I glass bottle container, and was subsequently stored in said container, the peptide retained a significant percentage of its initial potency (and binding affinity) after prolonged periods of storage at temperatures of 5 ° C, 25 ° C, 40 ° C, and even 55 ° C. The prevention of peptide degradation, and consequently, binding retention and binding affinity by storing the compositions of the present invention in a suitable container can be further improved. Although many different types of glass and some plastics have proven to be satisfactory, during long-term storage, steam-treated silicone bottles are preferred. Type 1 Plus steam-treated silicone bottles are available, for example from Schott of Lebanon, Pennsylvania, under the product name of Schott Type 1 Plus silica-coated bottles. Other suitable storage containers include USP Type 1 bottles, glass ampules and pre-packaged glass syringes Type 1. Some plastics have also been shown to be effective in aiding the stabilization of the peptide composition. In this regard, the preferred plastics are cyclic olefin copolymers, available for example from West Pharmaceuticals under the product name of CZ or Schott resin bottles under the product name of TopPAC bottles, or of Alean packaging under the product name. of serum bottles Ticona Topas. The compositions of the present invention can also be stored in PVC, as well as in flexible bags that are not PVC. When stored in the glass or plastic containers described above, the storage times described above at the storage temperatures described above can be achieved, although for storage periods of at least 18 months, Type I Plus bottles (steam-treated silicone) ) and Type I Plus glass ampoules are preferred. As shown, for example in FIGS. 3 and 4, storage of an aqueous composition of the present invention including about 5 μg / ml (FIG. 3) or 30 μg / ml (FIG. 4) of the motilin-like synthetic peptide of FIG. SEQ ID 1 sequence in Schott Type 1 bottles demonstrated stability (and maintained high potency levels) for several months when stored at temperatures of 5 ° C to 55 ° C. It will be appreciated by those skilled in the art that the measured stability of the pharmaceutical compositions at elevated temperatures, such as 40 ° C or higher, can serve as the anticipation bases of stability for longer periods at more typical storage temperatures, such as as 20 ° -25 ° C or 4 ° C-8 ° C, for example. Said "accelerated storage" studies are common in the field of the present invention.

Example 1 Stability of Mole Crawler SViotiBfn after Autoclave v Storage The motilin-like peptide of SEQ ID NO: 1 was dissolved in a concentration of 30 μg / ml in 10 mM sodium acetate buffer, pH 5.0. Samples of the peptide solution stored in Type I glass bottles were autoclaved at a temperature of 121 ° C for 15 minutes and the autoclave samples were incubated at a temperature of 5 ° C, 25 ° C, 40 ° C or 55 ° C. The potency of the peptide after storage at each temperature was measured over time by testing samples after incubation for one week, two weeks, three weeks, one month and three months. Potency was determined using HPLC to measure the amount of non-degraded peptide that remains in each sample. As shown in Figure 2, the peptide retained more than 90% potency after autoclaving and storage for 3 months, even at a high storage temperature of 55 ° C. The pharmaceutical composition of the present invention shows marked stability during the storage period even at a high storage temperature. Those skilled in the art will appreciate that the stability data obtained at said elevated temperatures (i.e. accelerated storage conditions) can be used to anticipate stability at temperatures of Minor, more typical storage for extended periods of time. EXAMPLE 2 Stability of Lyophilized Formulations of MotiBin-type Peptide Gompositions The motilin-type peptide including SEQ ID NO: 1 was dissolved in a concentration of 30 μg / ml in 10 mM citrate buffer and 1% w / v sucrose ( volume generation agent) at pH 6.0. The composition was lyophilized by standard techniques and stored in a 20 ml bottle at a temperature of 40 ° C. Motilin-like peptide potency was measured at the time intervals indicated in Figure 5, reconstituting the composition in water. Potency was determined using HPLC to measure the amount of non-degraded peptide that remains in each sample. As shown in Figure 5, the freeze-dried motilin peptide retained a significant power level (ie, greater than 90%) for several months. Similar results were obtained when the sucrose volume generating agent was replaced with a combined glycine of 0.04% w / v and mannitol volume generating agent of 0.4% w / v. Those skilled in the art will appreciate that the stability of pharmaceutical compositions at elevated temperatures, such as 40 ° C as shown in Figure 5, can serve as the basis of anticipation of stability during periods. longer at more typical storage temperatures, such as about 20 ° C-25 ° C or 4 ° C-8 ° C, for example. Whether prepared and stored as a buffered, ready-to-use or concentrated aqueous solution, or a lyophilized composition that is subsequently reconstituted, the pharmaceutical compositions of the present invention remain potent during storage over extended periods of time. The sustained potency of the peptide of about 90-100%, and in some cases greater than 95% during storage at temperatures of 5, 25, 40 and 55 ° C for at least 18 months, makes the pharmaceutical composition of the present invention a preferred means for the therapeutic delivery of motilin-like peptides. Although the present invention has been described within the context of its preferred embodiments, numerous modifications to such embodiments are possible without departing from the spirit of the present invention, which is set forth in the appended claims.

Claims (23)

1. REBV1MDDCACDONES 1. A pharmaceutical composition comprising: (a) from about 0.5 μg / ml to 100 mg / ml of a synthetic motilin-like peptide having no more than 16 amino acids and having the following structure: R2 Ri wherein: A is L-stereoisomer of a lipophilic aliphatic amino acid; B is L-proline or L-alanine; D is the L-stereoisomer of a lipophilic aliphatic amino acid; E is the L-stereoisomer of an aromatic amino acid, lipophilic aliphatic, or alicyclic; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine; J is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-GIn-Glu, Z-Leu-GIn-Glu-Lys, wherein Z is selected from the group consisting of D- arginine, D- homoarginine, D-glutamine, D-asparagine and D-alanine; RT is lower alkyl or allyl; R2 is selected from the group consisting of hydrogen, lower alkyl, propargyl and allyl; R3 is selected from the group consisting of hydrogen, lower alkyl and allyl; R 4 is cycloalkyl or aryl which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and lower alkoxy; R5 is selected from the group consisting of --CH2 C0NH2, aminoalkyl groups containing from 1 to 3 carbon atoms; and guanidinoalkyl groups containing from 2 to 3 carbon atoms; R6 is --COOH or --CONH2; and the symbol * represents an asymmetric carbon atom which may be in the D or L configuration, and wherein each lower alkyl group contains from 1 to 4 carbon atoms, provided that: (i) R5 is --CH2 CONH2 , only when J is Z-Leu or Z-Leu-GIn-Glu-Lys-Glu-Arg-Asn-Lys-Gly; (b) 5-250 mM of a buffer, the composition having a pH between 3 and 9 and having an osmolarity of about 10-500 mOsm / kg. 2. The composition as described in claim 1, characterized in that the synthetic peptide of molybdenum has 14 amino acids. 3. The composition as described in claim 1, characterized in that the synthetic motilin peptide is (Me3N) + Phe-Val-Pro-lle-Phe-Thr-Tyr-Gly-Glu-Leu-Gln-D-Arg-Leu -Lys-NH2. 4. The composition as described in claim 1, characterized in that the amino acid at position 12 of the motilin-like peptide is D-Arginine. 5. The composition as described in claim 1, characterized in that the buffer comprises sodium acetate / acetic acid. The composition as described in claim 1, characterized in that it comprises: (a) between 1 μg and 100 μg / ml microgram per milliliter of the motilin-type synthetic peptide; and (b) 10-100 mM of the buffer, the composition having a pH of about 4.5 to 5.5. The composition as described in claim 1, characterized in that the motilin-type synthetic peptide remains stable for at least 18 months when stored at 4 ° C-5 ° C. 8. The composition as described in claim 1, characterized in that it has been sterilized by autoclaving at a temperature of approximately 121 ° C-128 ° C. 9. The composition as described in claim 6, characterized in that the composition can be stored in a Type I bottle at a temperature of 55 ° C for at least 3 months and retains at least 90% of its peptide potency. 10. An aqueous pharmaceutical composition comprising a lipo motilin synthetic peptide having no more than 16 amino acids in a sodium acephalic / acetic acid buffer sterilized by steam sterilization at a temperature of 120-128 ° C, where the peptide retains at least about 95% of its initial potency after sterilization. 11. The composition as described in claim 10, characterized in that the composition can be stored at a temperature of up to 55 ° C for at least about 3 months and retain at least 90% of its initial potency after storage. 12. A stable aqueous pharmaceutical composition comprising a lipo motilin synthetic peptide having not more than 16 amino acids in an acetyl sodium / acetic acid amorigifuge wherein the composition, it can be stored for at least 9 months at a temperature of about 5 ° C-37 ° C, and retains at least about 90% of its initial potency. 13. The composition as described in claim 12, characterized in that it includes 1 μg / ml-100 μg / ml of the molybin-like peptide in approximately 10 mM of the amorigner. The composition as described in claim 1, prepared from a lyophilized formulation of the composition that has been reconstituted, wherein the composition further includes a volume generating agent. 15. The composition as described in claim 14, characterized in that it includes volume generating agents selected from the group consisting of sucrose, glycine and mannitol. 16. The composition as described in claim 15, characterized in that the volume generating agent is at a concentration of 1% w / v or less. 17. The composition as described in claim 15, characterized in that it comprises a volume generating agent that includes the combination of glycine and mannitol. 18. The composition as described in claim 12, stored in a flask coated with steam-vaporized silica. 19. The composition as described in claim 12, stored in a plastic container made of a material comprising a cyclic olefin copolymer. 20. The composition as described in claim 1, prepared from a concentrated solution of the amorphous synthetic peptide of the amorigner which has been diluted. 21. The composition as described in claim 20, characterized in that the concentrated solution includes up to 10 times the amount of the peptide and the buffer. 22. A concentrated aqueous pharmaceutical composition, including: a) a selected amount of a motilin-type synthetic peptide having no more than 16 amino acids and having the structure: R2 wherein: A is L-stereoisomer of a lipophilic aliphatic amino acid; B is L-proline or L-alanine; D is the L-stereoisomer of a lipophilic aliphatic amino acid; E is the L-stereoisomer of an aromatic amino acid, lipophilic aliphatic, or alicyclic; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine; J is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-GIn-Glu, Z-Leu-GIn-Glu-Lys, wherein Z is selected from the group consisting of D- arginine, D-homoarginine, D-glutamine, D-asparagine and D-alanine; R is lower alkyl or allyl; R2 is selected from the group consisting of hydrogen, lower alkyl, propargyl and allyl; R3 is selected from the group consisting of hydrogen, lower alkyl and allyl; R is cycloalkyl or aryl which can be unsubstituted or substiluted with one or more substituents selected from the group consisting of halogen, hydroxy and lower alkoxy; R5 is selected from the group consisting of --CH2 CONH2, aminoalkyl groups containing from 1 to 3 carbon atoms; and guanidinoalkyl groups containing from 2 to 3 carbon atoms; R6 is --COOH or --CONH2; and the symbol * represents an asymmetric carbon atom which may be in the configuration D or L, and wherein each lower alkyl group contains from 1 to 4 carbon atoms, provided that: (i) R5 is --CH2 CONH2, only when J is Z-Leu or Z-Leu-GIn-Glu -Lys-Glu-Arg-Asn-Lys-Gly; and b) a selected amount of a buffer, wherein at the time of dilution the diluted aqueous pharmaceutical composition comprises: i) 0.5 μg / ml to 100 μg / ml of the peptide; ii) 10-100 mM of the buffer; iii) has a pH between 3-9 and an osmolarity of about 10-500 mOsm / kg. 23. A lyophilized pharmaceutical composition that includes: a) a synthetic molybdenum peptide having no more than 16 amino acids, having the structure: R2 wherein: A is L-stereoisomer of a lipophilic aliphatic amino acid; B is L-proline or L-alanine; D is the L-stereoisomer of a lipophilic aliphatic amino acid; E is the L-stereoisomer of an aromatic amino acid, lipophilic aliphatic, or alicyclic; F is the L-stereoisomer of an aromatic or heteroaromatic amino acid; G is glycine or D-alanine; H is L-glutamic acid or L-glutamine; I is L-glutamine; J is selected from the group consisting of Z, Z-Leu, Z-Leu-Gln, Z-Leu-GIn-Glu, Z-Leu-GIn-Glu-Lys, wherein Z is selected from the group consisting of D- arginine, D-homoarginine, D-glutamine, D-asparagine and D-alanine; R- \ is lower alkyl or allyl; R2 is selected from the group consisting of hydrogen, lower alkyl, propargyl and allyl; R3 is selected from the group consisting of hydrogen, lower alkyl and allyl; R 4 is cycloalkyl or aryl which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, hydroxy and lower alkoxy; R5 is selected from the group consisting of --CH2 C? NH2, aminoalkyl groups containing from 1 to 3 carbon atoms; and guanidinoalkyl groups containing from 2 to 3 carbon atoms; R6 is --COOH or --CONH2; and the symbol * represents an asymmetric carbon atom which may be in the configuration D or L, and where each lower alkyl group contains from 1 to 4 carbon atoms, provided that: (i) R5 is --CH2 CONH2, only when J is Z-Leu or Z-Leu-GIn-Glu -Lys-Glu-Arg-Asn-Lys-Gly; whereby at the time of reconstitution, the reconstituted aqueous composition comprises: i) 0.5 μg / ml to 100 μg / ml of the peptide; ii) 10-200 mM of a buffer; iii) having a pH between 3-9 and an osmolarity of about 10-500 mOsm / kg. SUMMARY Stable pharmaceutical compositions are described which include a motilin-like synthetic peptide in a buffered solution. The composition provides a peptide that remains stable and that substantially retains its initial potency during prolonged storage and after steam sterilization.